Inhibition of nuclear factor-κB by 6-O-acetyl shanzhiside methyl ester protects brain against injury in a rat model of ischemia and reperfusion.

Abstract

BACKGROUND:

Recent studies have demonstrated an inflammatory response associated with the pathophysiology of cerebral ischemia. The beneficial effects of anti-inflammatory drugs in cerebral ischemia have been documented. When screening natural compounds for drug candidates in this category, we isolated 6-O-acetyl shanzhiside methyl ester (ND02), an iridoid glucoside compound, from the leaves of Lamiophlomis rotata (Benth.) Kudo. The objectives of this study were to determine the effects of ND02 on a cultured neuronal cell line, SH-SY5Y, in vitro, and on experimental ischemic stroke in vivo.

METHODS:

For TNF-α-stimulated SH-SY5Y cell line experiments in vitro, SH-SY5Y cells were pre-incubated with ND02 (20 μM or 40 μM) for 30 min and then incubated with TNF-α (20 ng/ml) for 15 min. For in vivo experiments, rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h followed by reperfusion for 23 h.

RESULTS:

ND02 treatment of SH-SY5Y cell lines blocked TNF-α-induced nuclear factor-κB (NF-κB) and IκB-α phosphorylation and increased Akt phosphorylation. LY294002 blocked TNF-α-induced phosphorylation of Akt and reduced the phosphorylation of both IκB-α and NF-κB. At doses higher than 10 mg/kg, ND02 had a significant neuroprotective effect in rats with cerebral ischemia and reperfusion (I/R). ND02 (25 mg/kg) demonstrated significant neuroprotective activity even after delayed administration 1 h, 3 h and 5 h after I/R. ND02, 25 mg/kg, attenuated histopathological damage, decreased cerebral Evans blue extravasation, inhibited NF-κB activation, and enhanced Akt phosphorylation.

CONCLUSION:

These data show that ND02 protects brain against I/R injury with a favorable therapeutic time-window by alleviating cerebral I/R injury and attenuating blood-brain barrier (BBB) breakdown, and that these protective effects may be due to blocking of neuronal inflammatory cascades through an Akt-dependent NF-κB signaling pathway.

• Authors: Wanglin Jiang, Shuping Zhang, Fenghua Fu, Haibo Zhu, Jian Hou
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 7 Pg. 55 (Sep 14 2010) ISSN: 1742-2094 [Electronic] England
• PMID: 20836895 (Publication Type: Journal Article)

Chemical References

• 6-O-acetylshanzhiside methyl ester
• Glucosides
• NF-kappa B
• Pyrans
• Tumor Necrosis Factor-alpha
• Proto-Oncogene Proteins c-akt

Topics

• Analysis of Variance
• Animals
• Blood-Brain Barrier (drug effects, metabolism, pathology)
• Blotting, Western
• Brain (drug effects, metabolism, pathology)
• Cell Line
• Cells, Cultured
• Glucosides (pharmacology)
• Humans
• Male
• NF-kappa B (antagonists & inhibitors, metabolism)
• Neurons (drug effects, metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrans (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (metabolism, pathology, prevention & control)
• Signal Transduction (drug effects)
• Stroke (metabolism, pathology)
• Tumor Necrosis Factor-alpha (metabolism, pharmacology)